microRNAs (miRNAs) are small regulatory RNAs that play important roles in development and disease1-3 and, thus, represent a potential new class of targets for therapeutic intervention4. Despite recent progress in silencing of miRNAs in rodents5,6, the development of effective and safe approaches for sequence-specific antagonism of microRNAs in vivo remains a significant scientific and therapeutic challenge. Moreover, there are no reports of miRNA antagonism in primates. Here we show that simple systemic delivery of an unconjugated, saline-formulated Locked Nucleic Acid-modified oligonucleotide (LNA-antimiR) effectively antagonizes the liver-expressed microRNA-122 in non-human primates. Acute administration by intravenous injections of 3 or 10 mg/kg LNA-antimiR to African green monkeys resulted in uptake of the LNA-antimiR in the cytoplasm of primate hepatocytes and formation of stable heteroduplexes between the LNA-antimiR and miR-122. This was accompanied by depletion of mature miR-122 and dose-dependent lowering of plasma cholesterol. Efficient silencing of miR-122 was achieved in primates by three doses of 10 mg/kg LNA-antimiR leading to long-lasting and reversible reduction of total plasma cholesterol without any evidence for LNA-associated toxicities or histopathological changes in the study animals. Our findings demonstrate the utility of systemically administered LNA-antimiRs in exploring microRNA function in rodents and primates and support the potential of such compounds as a novel class of therapeutics for disease-associated microRNAs. Further, the findings shows that pharmaceutical compositions comprising anti microRNA oligonucleotides of the invention, may be made and wherein the composition is made for administration to primates, and wherein the administration of maintenance dosis of the treatment can be made with a long time interval between each administration. Methods of treating diseases sensitive to treatment with anti microRNA oligonucleotides, using the compositions according to the invention are also provided.